Millions of people are exposed to arsenic-contaminated water in the U.S. and worldwide, and arsenic is ranked first on the most recent priority list of Superfund site hazardous substances. Current evidence suggests that lung cancer is the leading cause of arsenic-associated mortality. In addition, arsenic also increases the incidence of non-malignant pulmonary disease, and intriguing preliminary evidence obtained by our research group suggests that those exposed as young children or in utero are particularly susceptible to both the malignant and non-malignant pulmonary effects of arsenic. We propose a series of investigations to further explore the effects of childhood arsenic exposure and the mechanisms that may confer susceptibility to these effects. The proposed epidemiological studies include a case-control study of childhood and in utero arsenic exposure and subsequent risks of lung cancer in young adults in Northern Chile, and a cross-sectional study of lung function and respiratory health and arsenic exposure involving children in West Bengal. In addition, biological samples collected during these studies, combined with samples collected from several of our past studies, will be used for additional investigations on arsenic susceptibility and mechanisms of toxicity including: 1). Susceptibility related to individual differences in urinary concentrations of MMA3, a highly toxic but rarely studied arsenic metabolite; 2). Susceptibility related to genetic polymorphisms, in particular those involving AS3MT (cyt19), GSTO1, GSTM1, and EGFR. 3). Assessment of urinary proteomic patterns as biomarkers of exposure, disease, and susceptibility. In past years, Superfund has provided the core funding that has allowed us to make many new and important contributions to research on arsenic. Our goal is to continue this successful model, but with a new focus on the respiratory effects of childhood and in utero exposures and the associated mechanisms of toxicity and susceptibility. Given the widespread exposure to ingested arsenic in the U.S. and worldwide, and the very high risks of lung disease following early life exposures we have seen in our preliminary studies, investigating these effects has the potential to yield important new public health and scientific information regarding the in utero and childhood effects of toxic substances.